Neurokinin-1 receptor antagonists modulate brain noradrenaline and serotonin interactions.
Substance P (neurokinin-1; NK1) receptor antagonists represent a putative new class of antidepressant/anxiolytic drugs. Using in vivo electrophysiological paradigms in rats, this study examined the effects of acute, sub-acute and long-term administration of these drugs on the firing of rat noradrenaline and serotonin (5-HT) neurons. In the locus coeruleus, neither a 2-day treatment with the tachykinin NK1 receptor antagonists [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345, 10 mg/kg/day, i.p.), CP-99,994 (10 mg/kg/day, i.p.), nor a 14-day of treatment with (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 10 mg/kg/day, s.c.) significantly modified the firing rate of noradrenaline neurons. However, all these treatments attenuated the inhibitory action of the alpha(2)-adrenoceptor agonist clonidine on noradrenaline neuronal firing. While acute administration of the tachykinin NK1 receptor antagonist CP-96,345 (10 mg/kg, i.p.) attenuated the responsiveness of dorsal raphe 5-HT(1A) autoreceptors, lesioning noradrenaline neurons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) prevented the enhancing action of a 2-day treatment with CP-96,345 on 5-HT neuronal firing, suggesting that tachykinin NK1 receptor antagonists influence 5-HT system via noradrenaline neurons independently of their firing rate.
Haddjeri
Nasser
N
Université de Lyon, F-69373, Lyon, France. nhaddj@sante.univ-lyon1.fr
Blier
Pierre
P
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D004334:Drug Administration Schedule; D004594:Electrophysiology; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D044282:Receptor, Serotonin, 5-HT1A; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D012701:Serotonin; D003000:Clonidine; C066892:CP 96345; D009638:Norepinephrine